Compounds and compositions for inducing chondrogenesis

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof;or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds; and methods of using such compounds for treating joint damage or injury in a mammal, for inducing hyaline cartilage production or for inducing differentiation of chondrogenic progenitor cells into mature chondrocytes.

The invention claimed is: 
     
       1. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein: 
       
         
           
           
               
               
           
         
         R 1a  is hydroxyl; 
         R 2  is phenyl; a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocyclyl, each having 1 to 3 heteroatoms selected from N, O and S; wherein R 2  is unsubstituted or substituted by 1 to 3 substituents independently selected from halo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkoxy, cyano, C 1-6 alkylsulfonyl, phenyl unsubstituted or substituted by halo; 
         R 3  is a 5- or 6-membered heteroaryl having 1 to 2 heteroatoms selected from N, O and S; wherein R 3  is unsubstituted or substituted by 1 to 3 substituents independently selected from halo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, C 1-6 alkoxy or —NR 5 R 6 ; 
         R 5  and R 6  are independently hydrogen or C 1-6 alkyl; 
         alternatively, R 5  and R 6  together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl having 1-3 heteroatoms selected from N, O and S. 
       
     
     
       2. The compound of  claim 1 , wherein R 2  is phenyl, pyridyl, pyrazolyl, thiazolyl or piperidinyl, each of which is unsubstituted or substituted by 1 to 2 substituents independently selected from halo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, C 1-6  alkoxy, halo-substituted C 1-6 alkoxy, cyano, C 1-6 alkylsulfonyl, phenyl unsubstituted or substituted by halo. 
     
     
       3. The compound of  claim 1 , wherein R 2  is selected from:
 phenyl substituted by 3,4-dichloro; 2-trifluoromethyl; 3-trifluoromethyl; 3-cyano-4-chloro; 2-cyano-4-chloro; 3-fluoro-4-chloro; 3-trifluoromethoxy; 3-fluoro-4-trifluoromethoxy; or 3-chloro-4-(2-fluorophenyl); 
 pyridin-4-yl substituted by 6-methoxy or 2-trifluoromethyl; 
 pyridin-3-yl substituted by 5,6-dichloro; 6-methoxy; 5-chloro-6-methyl or 5-trifluoromethyl-6-methyl; 
 pyridin-2-yl substituted by 4,5-dichloro; 
 1H-pyrazol-3-yl substituted 1-methyl; 
 thiazol-2-yl substituted by 5-methyl; and 
 piperidin-4-yl substituted by 1-methylsulfonyl. 
 
     
     
       4. The compound of  claim 1 , wherein R 3  is selected from:
 pyridin-4-yl unsubstituted or substituted by 2-methyl; 2-trifluoromethyl; 2-methoxy; 2-amino; 2-fluoro; 2,3-difluoro; or 2,5-difluoro; 
 pyridin-3-yl unsubstituted or substituted by 6-methyl; 6-methoxy; or 5,6-dichloro; 
 pyridin-2-yl substituted by 6-trifluoromethyl; 
 pyrimidin-5-yl unsubstituted or substituted by 2-fluoro, 2-methyl, 2-amino, 2-trifluoromethyl, 2-morpholinyl or 2-di-methylamino; 
 pyrimidin-4-yl substituted by 2-methyl; and 
 1H-pyrazol-4-yl or 1H-pyrazolyl-3-yl substituted by 1-methyl. 
 
     
     
       5. The compound of  claim 1 , wherein R 3  is pyridyl unsubstituted or substituted by 1 to 2 substituents independently selected from fluoro, trifluoromethyl, methyl and methoxy. 
     
     
       6. The compound of  claim 1 , wherein said compound is (1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       7. The compound of  claim 1 , wherein said compound is (1S,2S,3R,4S,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       8. The compound of  claim 1 , wherein said compound is (1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       9. The compound of  claim 1 , wherein said compound is (1S,2S,3R,4S,5R)—N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       10. The compound of  claim 1 , wherein said compound is (1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       11. The compound of  claim 1 , wherein said compound is (1S,2S,3R,4S,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       12. A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. 
     
     
       13. A combination comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents. 
     
     
       14. A method for treating, ameliorating or preventing arthritis or joint injury, or for cartilage repair in a subject in need thereof, comprising administering a therapeutically effective amount of a compound according to  claim 1 , and optionally in combination with a second therapeutic agent; thereby treating, ameliorating or preventing arthritis or joint injury, or repairing cartilage, in said subject. 
     
     
       15. A method for treating or ameliorating osteoarthritis in a subject in need thereof, comprising administering a therapeutically effective amount of a compound according to  claim 1 , and optionally in combination with a second therapeutic agent; thereby treating or ameliorating osteoarthritis, in said subject. 
     
     
       16. The compound of  claim 1 , wherein R 3  is pyridyl, pyrimidinyl or pyrazolyl, each of which is unsubstituted or substituted by 1 to 2 substituents independently selected from halo, C 1-6 alkyl, halo-substituted C 1-6 alkyl, C 1-6 alkoxy or —NR 5 R 6 .